Insulin dependent diabetes mellitus (IDDM) in humans and NOD mice is an autoimmune disease caused by the selective destruction of pancreatic beta cells by autoreactive T lymphocytes. In addition to the well characterized loss of T-cell tolerance to islet autoantigens, the presence of anti-islet antibodies highlights a concomitant dysregulation of B-cell tolerance to these antigens. The requisite role of B-cells in diabetogenesis has recently been established in studies of B-cell deficient NOD mice which were found to be protected from insulitis and diabetes. Whether the role of B-cells in NOD diabetogenesis is mediated by the activated autoreactive B-cells and whether this role involves antigen presentation by B-cells in unknown. The investigator plans to study the mechanisms underlying the role of B-cells in NOD diabetogenesis. Thus, specific aim 1 will be focused on elucidating the contribution of MHC class I and class II mediated antigen presentation by B-cells to NOD diabetogenesis. In specific aim 2, studies are proposed to assess the contribution of the autoreactive subset of B- cells to NOD diabetogenesis by skewing the NOD B-cell repertoire away from diabetes associated Ig specificities. Specific aim 3 will address the importance of C3-mediated B-cell activation and antigen uptake in the development of anti-islet autoantibodies and diabetogenesis in NOD mice. In specific aim 4, the studies to be pursued aimed at elucidating the regulation of self-reactive B-cells in the NOD microenvironment. Insights into the mechanisms by which B-cells contribute to the etiology of autoimmune diabetes will provide the basis for the design of novel strategies for the prevention of IDDM.